RESUMEN
Pexidartinib (PLX3397) is a small molecule receptor tyrosine kinase inhibitor of colony stimulating factor 1 receptor (CSF1R) with moderate selectivity over other members of the platelet derived growth factor receptor family. It is approved for treatment of tenosynovial giant cell tumors (TGCT). CSF1R is highly expressed by microglia, which are macrophages of the central nervous system (CNS) that defend the CNS against injury and pathogens and contribute to synapse development and plasticity. Challenged by pathogens, apoptotic cells, debris, or inflammatory molecules they adopt a responsive state to propagate the inflammation and eventually return to a homeostatic state. The phenotypic switch may fail, and disease-associated microglia contribute to the pathophysiology in neurodegenerative or neuropsychiatric diseases or long-lasting detrimental brain inflammation after brain, spinal cord or nerve injury or ischemia/hemorrhage. Microglia also contribute to the growth permissive tumor microenvironment of glioblastoma (GBM). In rodents, continuous treatment for 1-2 weeks via pexidartinib food pellets leads to a depletion of microglia and subsequent repopulation from the remaining fraction, which is aided by peripheral monocytes that search empty niches for engraftment. The putative therapeutic benefit of such microglia depletion or forced renewal has been assessed in almost any rodent model of CNS disease or injury or GBM with heterogeneous outcomes, but a tendency of partial beneficial effects. So far, microglia monitoring e.g. via positron emission imaging is not standard of care for patients receiving Pexidartinib (e.g. for TGCT), so that the depletion and repopulation efficiency in humans is still largely unknown. Considering the virtuous functions of microglia, continuous depletion is likely no therapeutic option but short-lasting transient partial depletion to stimulate microglia renewal or replace microglia in genetic disease in combination with e.g. stem cell transplantation or as part of a multimodal concept in treatment of glioblastoma appears feasible. The present review provides an overview of the preclinical evidence pro and contra microglia depletion as a therapeutic approach.
Asunto(s)
Glioblastoma , Microglía , Humanos , Aminopiridinas/farmacología , Pirroles/metabolismo , Pirroles/farmacología , Microambiente TumoralRESUMEN
BACKGROUND: There is a need for early therapeutic interventions after traumatic brain injury (TBI) to prevent neurodegeneration. Microglia/macrophage (M/M) depletion and repopulation after treatment with colony stimulating factor 1 receptor (CSF1R) inhibitors reduces neurodegeneration. The present study investigates short- and long-term consequences after CSF1R inhibition during the early phase after TBI. METHODS: Sex-matched mice were subjected to TBI and CSF1R inhibition by PLX3397 for 5 days and sacrificed at 5 or 30 days post injury (dpi). Neurological deficits were monitored and brain tissues were examined for histo- and molecular pathological markers. RNAseq was performed with 30 dpi TBI samples. RESULTS: At 5 dpi, CSF1R inhibition attenuated the TBI-induced perilesional M/M increase and associated gene expressions by up to 50%. M/M attenuation did not affect structural brain damage at this time-point, impaired hematoma clearance, and had no effect on IL-1ß expression. At 30 dpi, following drug discontinuation at 5 dpi and M/M repopulation, CSF1R inhibition attenuated brain tissue loss regardless of sex, as well as hippocampal atrophy and thalamic neuronal loss in male mice. Selected gene markers of brain inflammation and apoptosis were reduced in males but increased in females after early CSF1R inhibition as compared to corresponding TBI vehicle groups. Neurological outcome in behaving mice was almost not affected. RNAseq and gene set enrichment analysis (GSEA) of injured brains at 30 dpi revealed more genes associated with dendritic spines and synapse function after early CSF1R inhibition as compared to vehicle, suggesting improved neuronal maintenance and recovery. In TBI vehicle mice, GSEA showed high oxidative phosphorylation, oxidoreductase activity and ribosomal biogenesis suggesting oxidative stress and increased abundance of metabolically highly active cells. More genes associated with immune processes and phagocytosis in PLX3397 treated females vs males, suggesting sex-specific differences in response to early CSF1R inhibition after TBI. CONCLUSIONS: M/M attenuation after CSF1R inhibition via PLX3397 during the early phase of TBI reduces long-term brain tissue loss, improves neuronal maintenance and fosters synapse recovery. Overall effects were not sex-specific but there is evidence that male mice benefit more than female mice.